The UCLA Pharmacogenetics and Pharmacogenomics Research Group (PPRG) has been developed to test the hypothesis that pharmacogenetic approaches can be used to optimize treatment strategies for common and complex disorders of public health relevance to Mexican-Americans, who are the poorest minority group in the U.S. To test this general hypothesis, we will address three specific aims: (1) To study pharmacogenetics in Mexican-Americans, using obesity and depression treatments as a proof of the concept that pharmacogenetic approaches can be used to optimize treatment strategies for common and complex disorders in this population. (2) To discover novel single nucleotide polymorphisms (SNPs) and test their relevance to the underlying genetic differences governing their responses to the pharmacological treatments conducted in Aim 1. (3) To phenotypically characterize gene-drug efforts in this application on two common and complex disorders of general medical interest and public health relevance, namely depression and obesity. These disorders represent independent risk factors for cardiovascular morbidity and mortality. There is considerable clinical, neurobiological, genetic, and pharmacological overlap between these two disorders, making it appropriate for the same center to study them. Our projects are highly synergist and were designed to inform and enrich one another. Specifically, Aim I will be addressed by prospective, clinical trials in which clinical outcomes and DNA will be collected by a team of highly experienced bilingual personnel with an outstanding track record of work with the Los Angeles Mexican-American community. Aim 2 will be achieved by use of Bayesian analysis to identify functional SNPs by measuring the evidence for polymorphism vs. simple sequencing errors, followed by high-throughput methods to confirm those SNPs and test their role in pharmacogenetic responses. Those methods include fluorescent polarizing genotyping, multiplexing microsphere arrays (GAMMArrays), and oligonucleotide arrays for SNP detection. Phenotyping will be done by studies of drug-gene interaction in existing transgenic animals as well as by generating novel BAC transgenic mice that overexpress SNPs that we find to be of interest to Aims I and 2. We are currently funded by the NIGMS, Pharmacogenetic Research Network and Knowledge Base (UO1GM6 1394) to conduct a one-year pilot study on the pharmacogenetics of depression in Mexican-Americans. This renewal application was designed to expand that effort from a pilot study to a full proposal that brings together a crossdisciplinary group of highly accomplished experts in order to create a unique pharmacogenetics resource for the Mexican-American community. Our accomplishments in the first three months of pilot funding demonstrate the feasibility of our program of research. Our data will be deposited in PharmacoGKB, GenBank, and dbSNP. Additionally, our clinical responses data and DNA samples will be deposited in the UCLA DNA Bank that is accessible to other investigators.